intensive insulin treatment issues in type 1 diabetes · intensive insulin treatment issues in type...

Intensive Insulin Treatment Issues in Type 1 Diabetes

Jay S. Skyler, MD, MACPJay S. Skyler, MD, MACPDivision of Endocrinology, Diabetes, and MetabolismDivision of Endocrinology, Diabetes, and Metabolism

and Diabetes Research Instituteand Diabetes Research InstituteUniversity of Miami Miller School of MedicineUniversity of Miami Miller School of Medicine

Commercial InterestsCommercial Interests• Board of Directors Member –Dexcom, Moerae Matrix, Paean

Therapeutics, VasoPrep Surgical• Scientific Advisory Board Member –

Diavacs, Halozyme, Orgenesis, Sekris, Valeritas, Viacyte

• Advisor or Consultant –Boheringer Ingelheim, Bristol-Myers Squibb/Astra-Zeneca, Elcelyx, Eli Lilly, Ideal Life, Intarcia, Julphar, Roche, Sanofi

• Stock or Option Holder –

Dexcom, Ideal Life, Moerae Matrix, Paean Therapeutics, Patton Medical Devices, Tandem Diabetes Care, VasoPrep Surgical

• Research Support (to University of Miami) –

Halozyme, Mesoblast

• Intensive Management of Type 1 Diabetes: Moshé

Phillip• How Big (Hypoglycemia) Is an Issue in T1D: Hans DeVries• Real Life Diabetes Management Issues Internist’s Perspective:

Richard Bergenstal• Real Life Diabetes Management Issues Pediatrician’s

Perspective: Desmond Schatz• Steps to a Perfect Close-Loop: Irl B. Hirsch• DREAM Project: Moshé

Phillip• Future of AP at Home: Hans DeVries • Role of CGM in Diabetes: Irl B. Hirsch• Role of SMBG and CGM –

REACT Study: Richard Bergenstal• New Basal and Prandial Insulin: Robert Ratner

Evolution ofEvolution of Intensive Insulin TherapyIntensive Insulin Therapy

Canadian Medical Association Journal 1922;12:141Canadian Medical Association Journal 1922;12:141--146. 146.

Toronto Daily Star, March 22, 1922.Toronto Daily Star, March 22, 1922.

RD Lawrence, 1925RD Lawrence, 1925

““The temperament and usual habits of the patient The temperament and usual habits of the patient should be considered in the type of treatment chosen should be considered in the type of treatment chosen and our object should be to interfere with these as and our object should be to interfere with these as little as is compatible with healthlittle as is compatible with health……

I know that full I know that full

physiological control of severe diabetes physiological control of severe diabetes –– the most the most

continuously normal blood sugar and the least continuously normal blood sugar and the least hypoglycaemia hypoglycaemia ––

can be best obtained with 4can be best obtained with 4––6 small 6 small

injections of soluble insulin in the 24 hoursinjections of soluble insulin in the 24 hours……

RD Lawrence. Diabetic Life, 1st edn. London: J & A Churchill LtdRD Lawrence. Diabetic Life, 1st edn. London: J & A Churchill Ltd, 1925 , 1925

Characteristics of Insulin PreparationsCharacteristics of Insulin Preparations

Purity of PreparationPurity of Preparation

Species of OriginSpecies of Origin

ConcentrationConcentration

Time Course of ActionTime Course of Action

OnsetOnset

PeakPeak

DurationDuration

Advances in Insulin PreparationsAdvances in Insulin Preparations

Protamine insulinate Protamine insulinate -- 19361936

Protamine zinc insulin Protamine zinc insulin -- 19361936

Surfen insulin Surfen insulin -- 19381938

Globin insulin Globin insulin -- 19391939

Phenylcarbomoyl insulin Phenylcarbomoyl insulin -- 19441944

Isophane (NPH) insulin Isophane (NPH) insulin -- 19461946

Lente insulins Lente insulins -- 19511951

Traditional Insulin PreparationsTraditional Insulin Preparations

ShortShort--actingacting

Regular (Soluble)Regular (Soluble)IntermediateIntermediate--actingacting

NPH (Isophane)NPH (Isophane)

Lente (Insulin Zinc Suspension)Lente (Insulin Zinc Suspension)LongLong--actingacting

Ultralente (Extended Insulin Zinc Suspension)Ultralente (Extended Insulin Zinc Suspension)

Protein Components in Insulin Preparations Pre-1972

%

Insulin Other

92%

8%

Purity of Insulin PreparationsPurity of Insulin Preparations

PreparationPreparation

Proinsulin ContentProinsulin Content(ppm)(ppm)

Conventional USPConventional USP

10,00010,000--40,00040,000““Single PeakSingle Peak””

300300--30003000

““Improved Single PeakImproved Single Peak””

< 50< 50““Single ComponentSingle Component””

< 10< 10

mg

% o

r U

/ml

mg

% o

r U

/ml

100100

00

1212 66 1212 66 1212

GLUCOSEGLUCOSE

INSULININSULIN

Breakfast Lunch Tea DinnerBreakfast Lunch Tea Dinner

Components of Insulin SecretionComponents of Insulin Secretion• Meal Related•• Meal RelatedMeal Related• Basal•• BasalBasal

Components of Insulin SecretionComponents of Insulin Secretion

Meal relatedMeal related

BasalBasal

Physiologic Serum Insulin Physiologic Serum Insulin Secretion ProfileSecretion Profile

4:004:00

2525

5050

7575

8:008:00 12:0012:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00

BreakfastBreakfast LunchLunch DinnerDinner

Plasma Plasma Insulin Insulin

((µµU/mL) U/mL)

TimeTime8:008:00

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00


8:008:0012:0012:008:008:00

TimeTime

REGREG REGREGNPHNPHNPHNPH

Classical Classical ““SplitSplit--MixedMixed”” Treatment ProgramTreatment Program

Plasma Plasma InsulinInsulin

GLUCOSEGLUCOSE

INSULININSULINmU/LmU/L

mg/dLmg/dL

100100

001212 66 1212 66 1212

BreakfastBreakfast LunchLunch SnackSnack DinnerDinner

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00


8:008:0012:0012:008:008:00TimeTime

REGREG REGREG

NPHNPHNPHNPH

““SplitSplit--MixedMixed”” Program WithProgram With

Bedtime Intermediate InsulinBedtime Intermediate Insulin


Typical Treatment ProgramTypical Treatment Program circa 1970circa 1970

•• Single Daily Injection Single Daily Injection -- NPH or LenteNPH or Lente

(Mixed Beef(Mixed Beef--Pork Pork -- U40 or U80) U40 or U80) ––

2424--25 g25 g




2424--25 g25 g

•• Meal Plan Meal Plan -- 3 meals, 3 snacks 3 meals, 3 snacks --

40% 40%

carbohyrate, 40% fat, 20% protein carbohyrate, 40% fat, 20% protein -- never skip meals, always eat on timenever skip meals, always eat on time

ENERGY ENERGY SOURCESOURCE(FOOD)(FOOD)

ENERGYENERGYUTILIZATIONUTILIZATION(ACTIVITY)(ACTIVITY)

INSULININSULIN




2424--25 g25 g

•• Meal Plan Meal Plan -- 3 meals, 3 snacks 3 meals, 3 snacks --

40% 40%

carbohyrate, 40% fat, 20% protein carbohyrate, 40% fat, 20% protein -- never skip meals, always eat on timenever skip meals, always eat on time

•• Urine Glucose TestingUrine Glucose Testing (first void or (first void or ““double voiddouble void””

?)?)

(Clinitest tablets with dropper)(Clinitest tablets with dropper)

Urine Glucose Testing ApproachesUrine Glucose Testing Approaches

0% 2%

Red cuprous oxide

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00



8:008:0012:0012:008:008:00TimeTime




•• SplitSplit--Mixed Insulin ScheduleMixed Insulin Schedule (Mixed Beef(Mixed Beef--Pork or Pure PorkPork or Pure Pork--

U100)U100)

•• Meal plan Meal plan -- 3 meals, 3 snacks 3 meals, 3 snacks --

4040--60% 60%

carbohyrate, 30% fat, 10carbohyrate, 30% fat, 10--20% protein20% protein•• Urine glucose testingUrine glucose testing

(first void or (first void or ““double voiddouble void”” ?)?)

(Clinitest tablets or Glucose oxidase (Clinitest tablets or Glucose oxidase test strips)test strips)

Could messy urine be avoided?Could messy urine be avoided?

Ted Danowski and colleagues

Diabetes Care. 1978 Jan 1; 1(1):27-33.

The First Article on SMBG

Karl Sussman – Patients WOULD NOT do it

Philip Felig – Patients COULD NOT do it

Leonard Madison – Patients SHOULD NOT do it

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00



8:008:0012:0012:008:008:00TimeTime



4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00


8:008:0012:0012:008:008:00TimeTime

REGREG REGREG

NPHNPHNPHNPH

““SplitSplit--MixedMixed”” Program WithProgram With

Bedtime Intermediate InsulinBedtime Intermediate Insulin


Basal/Bolus Insulin Absorption Pattern:Basal/Bolus Insulin Absorption Pattern:Standard Insulin PreparationsStandard Insulin Preparations

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00


8:008:0012:0012:008:008:00TimeTime

REGREG REGREGREGREG

NPHNPH


Basal/Bolus Insulin Absorption Pattern:Basal/Bolus Insulin Absorption Pattern:Standard Insulin PreparationsStandard Insulin Preparations

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00


8:008:0012:0012:008:008:00TimeTime

REGREG REGREGREGREG

NPHNPHNPHNPH


Intensive Insulin TherapyIntensive Insulin Therapy

System of Intensive Therapy of Type 1 DiabetesSystem of Intensive Therapy of Type 1 Diabetes

1. Multiple Component Insulin Program1. Multiple Component Insulin Program2. Careful Balance of Food Intake, Activity, & Insulin Dosage2. Careful Balance of Food Intake, Activity, & Insulin Dosage3. Daily Self3. Daily Self--monitoring of Blood Glucosemonitoring of Blood Glucose4. Planned Patient Alterations of Food Intake and of Insulin 4. Planned Patient Alterations of Food Intake and of Insulin

Dosage & TimingDosage & Timing5. Defined Target Blood Glucose Levels (Individualized)5. Defined Target Blood Glucose Levels (Individualized)6. Frequent Contact Between Patient and Staff6. Frequent Contact Between Patient and Staff7. Patient Education & Motivation7. Patient Education & Motivation8. Psychological Support8. Psychological Support9. Assessment (A1c)9. Assessment (A1c)

HbA1cHbA1c•• Integrated Measure of Glycemic ControlIntegrated Measure of Glycemic Control•• Correlates with Mean Blood GlucoseCorrelates with Mean Blood Glucose•• Patient Independent Assessment ToolPatient Independent Assessment Tool•• Facilitates ControlFacilitates Control•• Predicts ComplicationsPredicts Complications•• Reflects Tissue ChangesReflects Tissue Changes

Rate of progression of

retinopathy (per 100

patient-years)

5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5

A1c (%)

Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986.

0

2

4

6

8

10

DCCT: Absolute Risk of Sustained Retinopathy DCCT: Absolute Risk of Sustained Retinopathy Progression by Mean A1cProgression by Mean A1c

DCCT. N Engl J Med 1993;329:977DCCT. N Engl J Med 1993;329:977--8686

DCCT: Absolute Risk of Severe DCCT: Absolute Risk of Severe Hypoglycemia by Mean A1cHypoglycemia by Mean A1c

Rat

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Glycosylated Hemoglobin (%)Glycosylated Hemoglobin (%)

005.05.0 10.510.55.55.5 6.06.0 6.56.5 7.07.0 7.57.5 8.08.0 8.58.5 9.09.0 9.59.5 10.010.0

DCCT: 1986 to 1993DCCT: 1986 to 1993

Flexible Insulin TherapyFlexible Insulin Therapy

Principles of Flexible TherapyPrinciples of Flexible Therapy

Patient lifestyle determines treatment Patient lifestyle determines treatment programprogram

Meal pattern totally flexibleMeal pattern totally flexible——including including number of meals, timing of meals, content of number of meals, timing of meals, content of meals, variations from day to daymeals, variations from day to day

Unrestricted activity patternUnrestricted activity pattern——totally flexible, totally flexible, including sporadic exerciseincluding sporadic exercise

Unrestrained creativity in treatment optionsUnrestrained creativity in treatment options

Insulin program should be tailored to patient Insulin program should be tailored to patient lifestyle on ongoing basislifestyle on ongoing basis

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00


Ideal Basal/Bolus Insulin Ideal Basal/Bolus Insulin Absorption PatternAbsorption Pattern

8:008:0012:0012:008:008:00TimeTime


Advances in Insulin PreparationsAdvances in Insulin Preparations

Protamine insulinate Protamine insulinate -- 19361936

Protamine zinc insulin Protamine zinc insulin -- 19361936

Surfen insulin Surfen insulin -- 19381938

Globin insulin Globin insulin -- 19391939

Phenylcarbomoyl insulin Phenylcarbomoyl insulin -- 19441944

Isophane (NPH) insulin Isophane (NPH) insulin -- 19461946

Lente insulins Lente insulins –– 19511951

Rapid Acting Insulin Analogs Rapid Acting Insulin Analogs –– 1995 1995

Basal Insulin Analogs Basal Insulin Analogs –– 2000 2000

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00


RapidRapid--acting Insulin Analogs Provideacting Insulin Analogs ProvideIdeal Prandial Insulin ProfileIdeal Prandial Insulin Profile

8:008:0012:0012:008:008:00TimeTime

Lispro Lispro LisproLispro Lispro LisproAspart Aspart AspartAspart Aspart Aspart

oror orororor

Glulisine Glulisine GlulisineGlulisine Glulisine Glulisineoror ororororPlasma Plasma

InsulinInsulin

Four Questions Before Each MealFour Questions Before Each Meal

1.1.

What is my blood glucose level now?What is my blood glucose level now?2.2.

Do I plan to eat a larger or smaller Do I plan to eat a larger or smaller meal than usual?meal than usual?

3.3.

Will I be more or less active than Will I be more or less active than usual?usual?

4.4.

What has happened previously in What has happened previously in these circumstances?these circumstances?

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00


Ideal Basal/Bolus Insulin Ideal Basal/Bolus Insulin Absorption PatternAbsorption Pattern

8:008:0012:0012:008:008:00TimeTime


4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00



LongLong--acting Insulin Analogs Provideacting Insulin Analogs ProvideIdeal Basal Insulin ProfileIdeal Basal Insulin Profile

8:008:0012:0012:008:008:00TimeTime

GlargineGlargineoror

DetemirDetemir

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00


8:008:0012:0012:008:008:00TimeTime

GlargineGlargineoror

DetemirDetemir

Basal/Bolus Treatment Program WithBasal/Bolus Treatment Program With RapidRapid--acting and Longacting and Long--acting Analogsacting Analogs

Lispro Lispro LisproLispro Lispro LisproAspart Aspart AspartAspart Aspart Aspart

oror orororor

Glulisine Glulisine GlulisineGlulisine Glulisine Glulisineoror ororororPlasma Plasma

InsulinInsulin

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00


8:008:0012:0012:008:008:00TimeTime



4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00


8:008:0012:0012:008:008:00TimeTime



SnackSnack

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00


Variable Basal Rate ContinuousVariable Basal Rate ContinuousSubcutaneous Insulin Infusion (CSII) ProgramSubcutaneous Insulin Infusion (CSII) Program

8:008:0012:0012:008:008:00TimeTime

Basal InfusionBasal Infusion

BolusBolus BolusBolus BolusBolusPlasma Plasma InsulinInsulin

Dexcom G4 PlatinumDexcom G4 PlatinumContinuous Glucose MonitorContinuous Glucose Monitor

Change in A1c from Baseline to 26 Weeks in Change in A1c from Baseline to 26 Weeks in ≥≥7.0% HbA1c Cohort7.0% HbA1c Cohort

-0.50

0.02

-0.18 -0.21

-0.37

-0.22

-0.6-0.5-0.4-0.3-0.2-0.1

00.1

CGM Control CGM Control CGM Control

P<0.001P<0.001≥≥ 25 yr olds25 yr olds 1515--24 yr olds24 yr olds 88--14 yr olds14 yr olds

P=0.52P=0.52 P=0.29P=0.29

Cha

nge

in H

bA1c

Cha

nge

in H

bA1c

New Engl J Med 2008: 359: 1464New Engl J Med 2008: 359: 1464--14761476

Diabetes Care. 2009;32:1947-5193.

0.2

0.1

0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

-0.7

-0.8

P = 0.02P = 0.002

P <0.001

n = 1

n = 6 n = 43 n = 10 n = 29 n = 17 n = 7 n = 21 n = 28

Age ≥25 Age 15-24 Age 8-14

Change in A1C by Sensor UseC

hang

e in

A1C

Age (Years)

<4.0 days/week sensor use4.0-<6.0 days/week sensor use≥6.0 days/week sensor use


DCCT: Absolute Risk of Severe DCCT: Absolute Risk of Severe Hypoglycemia by Mean A1cHypoglycemia by Mean A1c

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005.05.0 10.510.55.55.5 6.06.0 6.56.5 7.07.0 7.57.5 8.08.0 8.58.5 9.09.0 9.59.5 10.010.0

DCCT: 1986 to 1993DCCT: 1986 to 1993

DCCT: 1986 to 1993DCCT: 1986 to 1993


Two Eras of Diabetes ManagementTwo Eras of Diabetes Management

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005.05.0 10.510.55.55.5 6.06.0 6.56.5 7.07.0 7.57.5 8.08.0 8.58.5 9.09.0 9.59.5 10.010.0

Control Group Control Group 20062006--20072007JDRF CGM StudyJDRF CGM Study

♦♦

JDRF. N Engl J Med JDRF. N Engl J Med 2008;359:14642008;359:1464--7676

■■■■

♦♦

■■♦♦ ♦♦

DCCT. N Engl J Med 1993;329:977DCCT. N Engl J Med 1993;329:977--86; JDRF. N Engl J Med 86; JDRF. N Engl J Med 2008;359:14642008;359:1464--76; Diabetes Care 2009: 32:137876; Diabetes Care 2009: 32:1378--1383 1383

Impact of Continuous Glucose Monitoring on Rate Impact of Continuous Glucose Monitoring on Rate of Severe Hypoglycemia Compared to DCCTof Severe Hypoglycemia Compared to DCCT

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005.05.0 10.510.55.55.5 6.06.0 6.56.5 7.07.0 7.57.5 8.08.0 8.58.5 9.09.0 9.59.5 10.010.0

■■ Age Age ≥≥ 25 years with A1C < 7.0% 25 years with A1C < 7.0% ■■ Age 8Age 8--14 years with A1C < 7.0 % 14 years with A1C < 7.0 % ■■ Age 15Age 15--24 years with A1C < 7.0% 24 years with A1C < 7.0% ♦♦ Age Age ≥≥ 25 years with A1C 25 years with A1C ≥≥ 7.0%7.0%♦♦ Age 15Age 15--24 years with A1C 24 years with A1C ≥≥ 7.0% 7.0% ♦♦ Age 8Age 8--14 years with A1C 14 years with A1C ≥≥ 7.0%7.0%

♦♦

Intensive Insulin TherapyIntensive Insulin Therapy WeWe’’ve Come A Long Wayve Come A Long Way

intensive insulin treatment issues in type 1 diabetes · intensive insulin treatment issues in type...

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